This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-MH-101* Biomarkers in Mental Disorders. Specifically, we plan to use a combination of genetic and neuroimaging tools to identify novel biomarkers of clinical severity in patients with schizophrenia. Schizophrenia is a chronic and severely debilitating mental disorder affecting approximately 1% of the world's population. Multiple neurotransmitter systems have been implicated, as well as both gray and white matter abnormalities. These structural alterations are thought to underlie both synaptic miscommunication at local neuronal circuits and functional disconnectivity among distributed brain regions. Given the role of myelin in sub-serving rapid long-distance communication, it has been proposed that a disruption of oligodendrocyte function and myelin integrity may contribute to some of the symptoms of this illness. Supporting this idea, an increasing number of neuropathological, neuroimaging and molecular genetic studies demonstrate the presence of white matter pathology in patients with schizophrenia. Although schizophrenia is not a dysmyelinating disorder, it is important to note that: a) the onset of symptoms usually coincides with the peak of myelination in the frontal and temporal lobes, b) patients with schizophrenia often show an impaired age- related increase in white matter volumes in the these brain regions and c) specific disruption of myelin structure during this critical period is often associated with schizophrenia-like symptoms. Over 90 articles in the past 5 years have used diffusion tensor imaging (DTI) to characterize white matter abnormalities in chronic and first episode patients. The studies demonstrated myelin integrity defects in the subcortical white matter, particularly in the frontal and temporal lobes. However given that these studies were performed using a small number of patients, and there were some discrepancies about the location and extent of white matter pathology identified, several questions remain about the prevalence of myelin pathology in the patient population. Furthermore, the genetic contributions to these alterations and the significance of white matter pathology to clinical severity remain to be established. As shown in the diagram above, in this challenge grant, we propose to assess influence of white matter alterations and genetic variation to the different symptoms of schizophrenia. The contributions of specific gene polymorphisms to measurements of white matter integrity will be evaluated using 500 patients and control subjects. These measurements will be correlated with disease severity using multivariate statistical methods developed by the PI. Specifically we plan to: Aim 1: Employ available DTI data and DNA samples, collected in 250 well-characterized schizophrenia patients and healthy controls, to identify the putative genetic underpinnings of white matter tract abnormalities and correlate these with several measurements of clinical severity. The data and samples have been collected as part of previously and currently funded studies at two sites: The Mind Research Network (MRN) and the Olin Neuropsychiatry Research Center (ONRC). Aim 2: Use additional data collected at both sites (N=250) to perform a confirmatory analysis validating the observations made under Aim 1. We will also release a set of software tools to the community. Why is a Challenge grant mechanism ideal for the proposed research? 1) Our goal of using innovative approaches to identify candidate biomarkers for mental disorders that are suitable for subsequent validation efforts matches the goals of this RFA. The proposed use of genetic, neuroimaging and statistical tools also matches the technological approaches described in the RFA and represents a new direction in the field. There are currently no reliable biomarkers for schizophrenia, so the proposed search for biomarkers that can predict disease severity is of high impact. 2) A two year grant award is ideal for the proposed work. We have already acquired most of the MRI data and collected saliva samples as part of other NIH funded studies that used different imaging modalities (fMRI and EEG) in the same groups of patients. Therefore, the project will focus on the genotyping and DTI analyses and the statistical methods to search for specific biomarkers. 3) We have assembled a team of investigators with unique expertise and an excellent record of effective past collaborations to pursue these studies. Our plan to hire and train new personnel, and to employ unique genome wide and bioinformatics technologies using US-based companies such as Illumina, Inc., will have the added benefit of stimulating the economy. PUBLIC HEALTH RELEVANCE: The goal of this Challenge grant application is to identify novel biomarkers of clinical severity in patients with schizophrenia. There are currently no reliable biomarkers for schizophrenia, so the proposed use of sophisticated genotyping, neuroimaging and biostatistical tools for searching biomarkers that can predict disease severity in two large cohorts of patient has a high clinical impact. The identification of such biomarkers will not only increase our knowledge of the pathophysiology of schizophrenia but also, and most importantly, may help predict an increased risk for this illness even before the onset of symptoms.